This invention relates to medical materials comprising synthetic macromolecular hydrogels. More particularly, it is concerned with wound-covering materials possessing characteristics far superior to those of prior-art natural or synthetic macromolecular materials.
Hydrogels (hydrous gels) are expected for use as medical materials because of their similarity to living tissues (hydrophilic) in many aspects such as soft touch and low irritation. Known hydrogels, however, find very limited use because, for example, of difficulties in molding due to being too soft or the inferior mechanical strength (see A. S. Hoffman et al., Trans. Amer. Soc. Artif. Intern. Organs, 18, 10 (1972)).
A variety of hardening procedures (means for improving the strength) have been proposed including treatment of mechanically weaker hydrogels with formaldehyde, glutaraldehyde, terephthalaldehyde or the like. However, much cannot be expected from the chemical treatment, the excellent properties of hydrogels (similarity in touch to living tissues, flexibility, elasticity, softness) usually become much worse by such chemical treatment. Moreover, use of a chemical reagent sometimes cause untoward reactions with living tissues (see D. L. MacKenzie et al., A.M.A. Archives Surgery, 77, 967 (1958)).
It is expected that irradiation will be the only means for hardening soft hydrogels without use of the chemical treatment (see N. A. Peppas et al., J. Biomed. Mater. Res., 4, 423 (1977), H. Singh et al., J. Sci. & Ind. Res., 39, March, 162 (1980)). However, the irradiation not only requires special equipment but also its effect is not so remarkable. In general, therefore, its practical application is difficult. By the application of irradiation, moreover, intrinsic superior characteristics of the hydrogels are often lost or deteriorated.
The present invention provides wound-healing cover materials which are superior in mechanical strength, elasticity, softness and touch, produce no irritation on the wound, are non-adhesive and of high permeability for the exudate.
This invention also provides wound-covering materials which, by embedding antimicrobials in the aforesaid hydrogels, have sustained-releasing capacity (long durable release) for the antimicrobial agent embedded to exert antimicrobial activities for a long period of time. In fact, the present invention provides wound-covering materials which effectively and continuously release an antimicrobial agent over a long period of time into the part (area) for which the microbial activities are desired, namely the contact surface of the wound surface with the covering material by embedding the antimicrobial agent in a hydrogel for medical use. There is not employed chemical reaction nor irradiation at all for hardening (improving the mechanical strength) in such a way as in the conventional processes so that no damage is produced on the microbial agent embedded.
Furthermore, this invention provides polyvinyl alcohol-hydrogel cold-preserving materials for medical use suitable for cooling the wound, particularly the wound part immediately after a burn.
The invention also provides wound-healing cover materials which are hardly deteriorated on air-drying after exposure to a lot of exudate (pus), that is, excellent in stability for durable contact with the wound surface.
Polyvinyl alcohol is employed as the starting material for the preparation of the above-mentioned medical materials. Although a number of procedures have been proposed for gelling polyvinyl alcohol (preparation of the hydrogels), all of the procedures involve problems in terms of the operation or of the properties of the product as summarized below.
(1) By air-drying an aqueous solution of polyvinyl alcohol there is obtained a wet or dry film, which, however, is merely a weak film inferior in water resistance and having no rigidity in water which finds only limited applications (see Japanese Patent Publication No. 9523/1965).
(2) Also by adding an acid to an aqueous suspension containing polyvinyl alcohol and tetraethyl silicate and air-drying the resulting mixture there is obtained a similar film to the above under (1) only. In this connection, it has also been proposed to freeze-dry the aqueous suspension to which an acid was added. The resulting film, however, is rather more inferior in strength and is scarcely moldable (see Japanese Patent Publications Nos. 30358/1980 and 11311/1980).
(3) A gelling method involving cobalt-60 (.gamma.-ray) irradiation of an aqueous solution of polyvinyl alcohol is well known. In this method, however, not only special equipment (equipment for the irradiation) is absolutely needed, so that cost for the irradiation is high, but also an additional hardening means (secondary hardening treatment) should often be applied because the resulting gel is too soft. Therefore, the gel obtained by this method is hardly utilizable except for special applications in which a highly viscous liquid (or a soft gel) is desired such as for the artificial vetreous body (intra-eyeball filling liquid (see J. Material Sci., 1974, 1815)).
(4) Also, it has long been well known that gellation of an aqueous solution of polyvinyl alcohol takes place promptly upon addition thereto of boric acid (or an aqueous solution of boric acid) or borax (or an aqueous solution of borax) (Note: Borax=sodium tetraborate decahydrate). The resulting gel, however, is so weak, fluid and readily splittable merely by touching with fingertips that the molded form is hardly retainable (see J. Am. Chem. Soc., 60, 1045 (1938), French Pat. No. 743942 (1933)).
Moreover, whereas the borax gel can exist under alkaline conditions, it will readily collapse at a pH not higher than 8. Therefore, the gel is hardly utilizable and of little value as medical material.
(5) A number of gellation methods have also been proposed for polyvinyl alcohol by the use of a phenol or an amino compound such as phenol, naphthol or Congo Red or a metallic compound such as of titanium, chromium or zirconium. These methods, however, have the same disadvantages as mentioned above under (4) (see Japanese Patent Publication No.9523/1965).
(6) It is also well known to form gels of polyvinyl alcohol using cross-linking agents or copolymerizing components such as aldehydes, dialdehydes, unsaturated nitriles, diisocyanates, trimethylolmelamine, epichlorohydrin, bis-(.beta.-hydroxyethylsulfone), polyacrylic acid, dimethylolurea and maleic anhydride. In this process, however, not only an operation using chemical reagents is needed, but also it is difficult to obtain a strong gel of a high water content (see Textile Res. J., (3), 189 (1962), British Pat. No.742,900 (1958)).
(7) Also, it has long been well known to form the gels by allowing an aqueous solution of polyvinyl alcohol to stand at a low temperature not higher than 40.degree. C., particularly from 5 to 18.degree. C.
However, the gels formed around room temperature are fragile like agar and carrageenan. Besides, they will be in solution merely by stirring vigorously, by adding water followed by stirring, or by warming gently.
It is also well known that low temperatures are preferable to produce gels from an aqueous solution of polyvinyl alcohol by cooling. For example, it is known to conduct the operation at 18.degree. C., or at a temperature as low as 0.degree. C. or below (see Polymer J., 6, 103 (1974)).
In any case, however, the gels obtained are agar-, carrageenan- or jelly-like weak gels (or viscous liquids) and are very sticky. Moreover, these gels are so poor in water resistance that they will be swollen in water to a remarkable extent, further softened and partly dissolved out into water to leave the remainder in paste. Furthermore, in water or in warm water at 40.degree.-50.degree. C., more rapid deformation takes place to produce an aqueous dispersion or solution. Because of these disadvantages, they have little value as medical materials.
(8) It is also known to prepare gels by adding a small amount of polyvinyl alcohol to an aqueous solution of a water-soluble macromolecular material such as, for example, agarose, agar, albumin, alginate, curdlan, carrageenan, casein, CMC, furcellaran, gelatin, methylcellulose, pectin, starch, tamarind gum, xanthan gum, tragacanth gum and guar gum and allowing the mixture to cool, immersing it in a gellating agent-containing bath (a coagulation bath) or freeze-drying it (see Japanese Patent Publication Nos. 25210 and 25211/1981. By such a process, however, there is obtained merely a weak and poorly water-resistant viscous liquid or non-fluid gel or a loose water-soluble dry powder (freeze-dried powder).
(9) It is also well known that a gel is formed by adding a minimum amount (0.1-0.2% by weight) of polyvinyl alcohol to kaolin or bentonite. On the basis of this principle, a variety of well-known attempts have been made to modify the surface soil of a stadium by scattering polyvinyl alcohol (a diluted aqueous solution) over it to make it less dusty, to improve water permeability or water retention of the field soil by scattering a small amount of polyvinyl alcohol (a diluted aqueous solution) over it, or to promote flocculation and precipitation of clay (colloidal particles) by adding a small amount of polyvinyl alcohol to muddy water. The gels formed by these techniques, however, are also very fragile (hardly distinguishable from soil in appearance) and easily collapse even in dry powder, not to mention in water so that they will poorly be valuable as medical materials.
As a result of studies to develop an inexpensive and consistent process for preparing water-insoluble gels using polyvinyl alcohol which are high in mechanical strength, elasticity and softness, good in touch, excellent in capacity of removing the exudate from the wound part, additionally being non-adhesive to it, will not be stiffened on air-drying, will neither be frozen nor stiffened even when stored in a refrigerator, and will hardly be deteriorated when air-dried after exposure to much exudate from the wound surface (wound part), we have found that the above-mentioned objectives are achieved to give excellent covering materials being non-irritative to the wound part by pouring an aqueous solution containing a polyvinyl alcohol with specific properties, a water-soluble C.sub.2-20 polyhydric alcohol having 2-8 hydroxyl groups in the molecule and a high-viscosity water-soluble macromolecular substance being different from the polyvinyl alcohol onto a mold having a large number of projections on the surface which solution is cooled, solidified, shaped and then partly dehydrated under vacuum, and completed the present invention.